Summary psychopharmacology chapter 10

What is the effect of alcohol on the body? - Chapter 10

Alcohol

Alcohol is the most abused drug in the world. Given the availability and the large percentage of the population that uses it, it is not surprising that alcohol leads to the most common substance abuse disorder.

Distillation is a process in which alcohol is separated from other fermentation products by heating it. Although distillation can result in pure ethyl alcohol (ethanol), most spirits contain 40-50 percent alcohol.

What is the pharmacology of alcohol?

Absorption

Alcohol or ethanol is both soluble in water and fat and can easily spread through all cell membranes. Higher alcohol concentrations (stronger drinks) spread faster than lower ones. Ethanol passes the blood-brain barrier quickly, and peaks in plasma concentrations are reached between 30 to 60 minutes. The presence of food in the stomach and intestines slows the distribution of alcohol. The wall of the small intestine absorbs approximately eighty percent and the remainder will be absorbed by the stomach or is almost immediately excreted by perspiration, breathing or urine. Because all tissues, including the placenta, absorb alcohol so easily, a pregnant woman exposes her fetus to blood levels similar to their own.

The blood alcohol concentration (BAC) is expressed in the number of grams of alcohol per hundred milliliters of blood. A breath test can immediately determine the BAC by analyzing the breath of an individual. The breath contains alcohol that got into the lungs through the bloodstream. With a BAC of 0.06-0.1 you already have a much higher reaction time, problems with attention, reduced control over movements and significant limitations in cognitive functioning. With a BAC of 0.3-0.39 it becomes already very dangerous and you can get fatal symptoms. Above 0.4 it can be fatal.

Metabolism

Alcohol metabolism starts immediately after consumption. Approximately 90-95 percent of the alcohol is metabolized by the enzyme group alcohol dehydrogenase. The remaining five to ten percent is excreted by perspiration and breathing or is metabolized by another liver enzyme. This enzyme is called P450 and is essential for oxygen reactions that are involved in metabolism. Only a small fraction of alcohol is excreted via the urine.

Small amounts of alcohol dehydrogenase immediately begins to metabolize alcohol in the stomach. When alcohol enters the small intestine, it is quickly absorbed into the blood supply. This way it ends up in the liver, where the remaining part (80-85 percent) is metabolized. First-pass metabolism is alcohol that is metabolized by stomach and liver enzymes before it can reach the tissues. About 25-30 percent of the ingested alcohol falls below. The amount of metabolized alcohol depends on the availability of alcohol dehydrogenase and the coenzyme nicotinamide adenine dinucleotide (NAD). This coenzyme can be seen as a rate-limiting enzyme, because availability determines the rate of alcohol metabolism. Because men and women have different levels of alcohol dehydrogenase, they metabolize alcohol in different speeds. Because women have less stomach alcohol dehydrogenase and a higher fat-alcohol ratio, they have larger blood concentrations than men for equal doses of alcohol.

In the first phase of metabolism, alcohol is converted into acetylhyde, which is very toxic. This is rapidly metabolized in acetic acid by the enzyme aldehyde dehydrogenase. Genetic variations in the form and expression of this enzyme can have a major influence on alcohol metabolism. The disulfiram (Antabuse) agent inhibits aldehyde hydrogenase and causes nausea, vomiting, sweating, dizziness and severe headaches in alcoholics to discourage drinking.

What effects does alcohol have on the body?

Because alcohol is both soluble in fat and water, it has an effect on a wide range of cellular functions and systems. The non-specific effects of alcohol on neuronal functioning include the effects on all cellular membranes. Because alcohol dissolves in the lipid cell membrane, it disrupts multiple cell processes.

Previously people believed that the main mechanism of action of alcohol was membrane fluidization. It was assumed that alcohol dissolves in cell membranes to make them more fluid. This fluidization would disrupt multiple membrane processes including the movement of ions through channels, the conduction of membrane potentials and the delivery and storage of neurotransmitters. Although membrane fluidization appears to be responsible for high levels of dampening and narcotic effects (at high doses) of alcohol, it is not the cause of many other effects (mainly at low doses), including euphoria, cognitive and motor disturbances and anxiolysis.

Neurotransmitter systems

Alcohol has an agonistic effect on GABA receptors, specifically on the GABA A receptor. Many of the behavioral effects of alcohol are mediated by increased GABA activity. The drug Ro15-4513 is a strong competitive antagonist for the effects of alcohol. Because this agent binds competitively to the delta receptor, it is assumed that alcohol also has an affinity with this receptor subtype.

Chronic exposure to alcohol during pregnancy causes brain damage that keeps developing and causes the fetal alcohol syndrome (FAS). Upregulation of fetal GABA A receptor expression in the cerebral cortex and hippocampus contributes to this syndrome. A characteristic symptom of FAS is abnormal cortical morphology and development.

Glutamate

With high concentrations, alcohol is a strong antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. These receptors are widely distributed throughout the brain and spinal cord and play an important role in learning and memory and in the general irritability of cortical neurons. NDMA receptors are all ligand-gated receptors, which means that the ion current only occurs when a neurotransmitter is bound to it. The antagonism of alcohol at NDMA receptors also contributes to memory loss effects in median doses and blackouts at higher doses. Chronic exposure to alcohol contributes to the NDMA receptor upregulation, which seems to provide for intensified activity in the central nervous system and for strokes that are often observed during periods of abstinence and alcohol withdrawal.

Dopamine

Alcohol has a strong effect on dopamine activity in the mesolimbic system. Intake of intoxicating alcohol doses increases the dopamine release in the ventral tegmental area and the nucleus accumbens. The mechanisms by which alcohol increases dopamine release are unknown. Recent research shows that alcohol has a biphasic effect on dopamine activity. Alcohol causes an increase in dopamine excitability in the mesolimbic system, followed by GABA mediated inhibition. Although alcohol affects dopamine, it is less addictive than cocaine and amphetamine.

Opioids

Acute administration of alcohol also increases opioid activity in different brain areas, including the VAT. At least part of the effects of alcohol on dopamine neurons are mediated by opioid suppression of GABA-ergic inhibition. Alcohol thus influences the activity of most major neurotransmitter systems. This influence is directly when it comes to glutamate and GABA and indirectly when it comes to opioids and dopamine. Due to the wide range of non-specific effects on these systems, it is still unclear how alcohol effects these systems.

When does alcohol tolerance arise?

The development of tolerance of alcohol depends on the drinking pattern and the amount of drink that has been drank. Heavy, frequent drinkers develop tolerance fairly quickly compared to sporadic drinkers. There is a cross-tolerance when drugs share the same action mechanisms. For example, people who have developed tolerance to benzodiazepines also show tolerance to alcohol, even if they have never drank alcohol.

Metabolism tolerance

There is a metabolic tolerance position as alcohol compensatory increases in the liver and P450 is produced. These enzymes metabolize ninety percent of all alcohol. Metabolic tolerance contributes approximately 25% to the tolerance for alcohol.

Cellular tolerance

Different changes in neuronal functioning are subject to cellular tolerance , including receptor and cAMP downregulation. Tolerance appears to be the result of the fact that specific GABA A receptor subtypes no longer manifest on cell surfaces. Differences in GABA A receptor expression may be responsible for the differences symptoms of withdrawal symptoms after chronic alcohol consumption.

Behavioral tolerance

Tolerance for the motor effects of alcohol is called behavioral tolerance. Animal studies show that behavioral tolerance for alcohol can be learned. This learning process seems to relate to movement coordination (operant conditioning) in the presence of 'alcohol onset cues'. Another term for behavioral tolerance is 'state-depended-learning' since it performs better when tested under the same physiological or drug conditions as the test animals were during training.  

Associative tolerance

Associative tolerance refers to Pavlovian conditioning reactions that are evoked by 'drug onset cues'. It is believed that these evoked responses are related to rapid internalization of receptors, making less available for the binding of drugs or neurotransmitters. What exactly happens in the synapses is not yet known, but glutamate NMDA receptors seem to be involved.

When is someone dependent of alcohol?

Alcohol dependency is a pattern of symptoms observed during alcohol withdrawal after chronic use. The duration and severity of these symptoms depend on the duration and intensity of alcohol consumption and the genetic factors controlling neuronal changes. Symptoms include nausea, vomiting, headache, sweating, shaking or trembling and strokes during the period of abstinence.

Delirium tremens can occur in severe cases of long-term alcohol consumption. Symptoms of this include confusion, fever, irritation, hypertension and tachycardia. If it is not treated, it can be fatal in 35% of cases.

Pharmacological treatment

Benzodiazepines can reduce the severity of withdrawal symptoms through the similarity in the action mechanism. The CB1 Receptor antagonist Rimonabant (SR141716) reduces the voluntary alcohol intake in both humans and animals. Drugs used in an alcohol addiction are: diazepam (valium), Naltrexone, acamprosate, disulfiram (antabuse), bupropion (Wellbutrin), fluoxetine (SSRIs) and Rimonabant (SR141716).